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Diabetes 54:2946-2951, 2005
© 2005 by the American Diabetes Association, Inc.

Serum Glucagon Counterregulatory Hormonal Response to Hypoglycemia Is Blunted in Congenital Hyperinsulinism

Khalid Hussain1, Joseph Bryan2, Henrick T. Christesen3, Klaus Brusgaard3, and Lydia Aguilar-Bryan2,4

1 The London Centre for Pediatric Endocrinology and Metabolism, Great Ormond Street Hospital for Children National Health Service Trust and the Institute of Child Health, University College London, U.K
2 Department of Molecular and Cellular Biology, Baylor College of Medicine Houston, Texas
3 Department of Pediatrics/Genetics, University Hospital Odense, Denmark
4 Department of Medicine, Baylor College of Medicine Houston, Texas

The mechanisms involved in the release of glucagon in response to hypoglycemia are unclear. Proposed mechanisms include the activation of the autonomic nervous system via glucose-sensing neurons in the central nervous system, via the regulation of glucagon secretion by intra-islet insulin and zinc concentrations, or via direct ionic control, all mechanisms that involve high-affinity sulfonylurea receptor/inwardly rectifying potassium channel-type ATP-sensitive K+ channels. Patients with congenital hyperinsulinism provide a unique physiological model to understand glucagon regulation. In this study, we compare serum glucagon responses to hyperinsulinemic hypoglycemia versus nonhyperinsulinemic hypoglycemia. In the patient group (n = 20), the mean serum glucagon value during hyperinsulinemic hypoglycemia was 17.6 ± 5.7 ng/l compared with 59.4 ± 7.8 ng/l in the control group (n = 15) with nonhyperinsulinemic hypoglycemia (P < 0.01). There was no difference between the serum glucagon responses in children with diffuse, focal, and diazoxide-responsive forms of hyperinsulinism. The mean serum epinephrine and norepinephrine concentrations in the hyperinsulinemic group were 2,779 ± 431 pmol/l and 2.9 ± 0.7 nmol/l and appropriately rose despite the blunted glucagon response. In conclusion, the loss of ATP-sensitive K+ channels and or elevated intraislet insulin cannot explain the blunted glucagon release in all patients with congenital hyperinsulinism. Other possible mechanisms such as the suppressive effect of prolonged hyperinsulinemia on {alpha}-cell secretion should be considered.

Address correspondence and reprint requests to Khalid Hussain, The Institute of Child Health, Biochemistry Endocrinology and Metabolism Unit, University College London, 30 Guilford Street, London WC1N 1EH, U.K. E-mail: k.hussain{at}ich.ucl.ac.uk

Abbreviations: ABCC8, ATP-binding cassette, subfamily C, member 8 (high-affinity sulfonylurea receptor); CHI, congenital hyperinsulinism; KATP channel, ATP-sensitive K+ channel; KCNJ11, inwardly rectifying potassium channel, subfamily J, member 11; KIR6.2, inwardly rectifying potassium channel; NEFA, nonesterified fatty acid; SUR1, high-affinity sulfonylurea receptor; VMH, ventromedial hypothalamus


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Copyright © 2005 by the American Diabetes Association.